Abnormal interneuron development in disrupted-in-schizophrenia-1 L100P mutant mice

BACKGROUND: Interneuron deficits are one of the most consistent findings in post-mortem studies of schizophrenia patients and are likely important in the cognitive deficits associated with schizophrenia. Disrupted-in-Schizophrenia 1 (DISC1), a strong susceptibility gene for schizophrenia and other mental illnesses, is involved in neurodevelopment, including that of interneurons. However, the mechanism by which DISC1 regulates interneuron development remains unknown. In this study, we analyzed interneuron histology in the Disc1-L100P single point mutation mouse, that was previously shown to have behavioral abnormalities and cortical developmental defects related to schizophrenia. RESULTS: We sought to determine whether a Disc1-L100P point mutation in the mouse would alter interneuron density and location. First, we examined interneuron position in the developing mouse cortex during embryonic days 14–16 as an indicator of interneuron tangential migration, and found striking migration deficits in Disc1-L100P mutants. Further analysis of adult brains revealed that the Disc1-L100P mutants have selective alterations of calbindin- and parvalbumin-expressing interneurons in the cortex and hippocampus, decreased GAD67/PV co-localization and mis-positioned interneurons across the neocortex when compared to wild-type littermates. CONCLUSION: Our results are consistent with the anomalies seen in post-mortem schizophrenia studies and other Disc1 mutant mouse models. Future research is required to determine the specific mechanisms underlying these cellular deficits. Overall, these findings provide further evidence that DISC1 participates in interneuron development and add to our understanding of how DISC1 variants can affect susceptibility to psychiatric illness

the effect of ethnicity and immigration on treatment resistance in schizophrenia

Background: Treatment resistance is a common issue among schizophrenia patients undergoing antipsychotic treatment. According to the American Psychiatric Association (APA) guidelines, treatment-resistant status is defined as little or no symptom reduction to at least two antipsychotics at a therapeutic dose for a trial of at least six weeks. The aim of the current study is to determine whether ethnicity and migration are associated with treatment resistance. Methods: In a sample of 251 participants with schizophrenia spectrum disorders, we conducted cross-sectional assessments to collect information regarding self-identified ethnicity, immigration and treatment history. Ancestry was identified using 292 markers overlapping with the HapMap project. Using a regression analysis, we tested whether a history of migration, ethnicity or genetic ancestry were predictive of treatment resistance. Results: Our logistic regression model revealed no significant association between immigration (OR = 0.04; 95%CI = 0.35–3.07; p = 0.93) and treatment resistant schizophrenia. White Europeans did not show significant association with resistance status regardless of whether ethnicity was determined by self-report (OR = 1.89; 95%CI = 0.89–4.20; p = 0.105) or genetic analysis (OR = −0.73; 95%CI = −0.18–2.97; p = 0.667). Conclusion: Neither ethnicity nor migrant status was significantly associated with treatment resistance in this Canadian study. However, these conclusions are limited by the small sample size of our investigation. Keywords: Schizophrenia, Treatment resistance, Antipsychotics, Ethnicity, Migratio

Investigation of the HSPG2 Gene in Tardive Dyskinesia – New Data and Meta-Analysis

Tardive dyskinesia (TD) is a movement disorder that may occur after extended use of antipsychotic medications. The etiopathophysiology is unclear; however, genetic factors play an important role. The Perlecan (HSPG2) gene was found to be significantly associated with TD in Japanese schizophrenia patients, and this association was subsequently replicated by an independent research group. To add to the evidence for this gene in TD, we conducted a meta-analysis specific to the relationship of HSPG2 rs2445142 with TD occurrence, while also adding our unpublished genotype data. Overall, we found a significant association of the G allele with TD occurrence (p = 0.0001); however, much of the effect appeared to originate from the discovery dataset. Nonetheless, most study samples exhibit the same trend of association with TD for the G allele. Our findings encourage further genetic and molecular studies of HSPG2 in TD

Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. (“GUIDED”), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian “GAPP-MDD” RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477)

Investigation of the genetic interaction between BDNF and DRD3 genes in suicidical behaviour in psychiatric disorders

Suicide is a serious public health concern, and it is partly genetic. The brain-derived neurotrophic factor (BDNF) gene has been a strong candidate in genetic studies of suicide (Zai et al, 2012; Dwivedi et al, 2010) and BDNF regulates the expression of the dopamine D3 receptor

Exploring the association between brain-derived neurotrophic factor (BDNF) levels and longitudinal psychopathological and cognitive changes in Sardinian psychotic patients

Background and Hypothesis: Schizophrenia is among the most debilitating mental disorders and has complex pathophysiological underpinnings. There is growing evidence that brain-derived neurotrophic factor (BDNF) can play a role in its pathogenesis. The present study investigated the longitudinal variation of serum BDNF levels in a 24-month observational prospective cohort study of Sardinian psychotic patients and its relationship with psychopathological and cognitive changes. Further, we examined whether genetic variation within the BDNF gene could moderate these relationships. Study design: Every six months 105 patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and social measures. We performed a targeted analysis of four tag single nucleotide polymorphisms (SNPs) within the BDNF gene that were selected and analyzed using Polymerase Chain Reaction (PCR). Longitudinal data were analyzed using mixed-effects linear regression models (MLRM). Study results: We observed a declining longitudinal trajectory of BDNF levels in psychotic patients in general, and in relation to the severity of depressive and negative symptoms. BDNF serum levels also declined in patients scoring lower in cognitive measures such as attention and speed of information processing and verbal fluency. The rs7934165 polymorphism moderated the significant association between verbal fluency and BDNF levels. Conclusions: These findings in patients from real-world settings suggest a plausible role of peripheral BDNF levels as a marker of illness burden in schizophrenia spectrum disorders

Converging Evidence Points to BDNF as Biomarker of Depressive Symptoms in Schizophrenia-Spectrum Disorders

Brain-derived neurotrophic factor (BDNF) is a key modulator of neuroplasticity and has an important role in determining the susceptibility to severe psychiatric disorder with a significant neurodevelopmental component such as major psychoses. Indeed, a potential association between BDNF serum levels and schizophrenia (SCZ) and schizoaffective disorder (SAD) has been tested in diverse studies and a considerable amount of them found reduced BDNF levels in these disorders. Here, we aimed at testing the association of BDNF serum levels with several demographic, clinical, and psychometric measures in 105 patients with SCZ and SAD, assessing the moderating effect of genetic variants within the BDNF gene. We also verified whether peripheral BDNF levels differed between patients with SCZ and SAD. Our findings revealed that BDNF serum levels are significantly lower in patients affected by SCZ and SAD presenting more severe depressive symptomatology. This finding awaits replication in future independent studies and points to BDNF as a possible prognostic indicator in major psychoses